Long Noncoding RNAs as Functional Drivers of Breast Cancer Invasion
Abstract
Increased emphasis on breast cancer screening has led to a dramatic increase in diagnosis of precancerous ductal carcinoma in situ (DCIS) over the past 30 years. Unfortunately, diagnosis of late-stage invasive and metastatic disease has not proportionally declined. This suggests that not all women diagnosed with DCIS would have developed a life-threatening cancer. In fact, DCIS may never progress. Because we do not currently understand what causes the progression to metastatic, life-threatening cancer, all women diagnosed with DCIS will undergo an aggressive treatment strategy including invasive lumpectomy or mastectomy coupled with radiation therapy. These treatment methods, while effective, are unnecessary for tens of thousands of women per year in the United States alone. We aim to understand the difference between those benign DCIS tumors and those breast tumors that are life-threatening. Successful completion of this project will lead to the provision of treatment to only the subset of patients whose DCIS is likely to progress to invasive breast cancer. In collaboration with Dr. Behbod at the University of Kansas Medical Center, we have tumor biopsy samples from women that have both early-stage DCIS and progressed, invasive breast cancer in the same breast. These matched samples allow us to directly evaluate the difference between the precancerous and invasive disease and identify changes in gene expression. From these samples, we have identified a group of genes called long noncoding RNAs (lncRNAs) that are enriched in the invasive samples. The function of lncRNAs is largely unknown; however, they are being discovered as critical regulators of gene expression and tumorigenesis. Therefore, lncRNAs represent a rich source of potential cancer drivers. In this project, we will evaluate the role of a lncRNA (BHLHE40-AS1) that is enriched in patient invasive tumors relative to matched precursor lesions in driving breast cancer progression. We will further test BHLHE40-AS1 in a mouse model to determine if our findings in the lab also occur in a living system. Further, we will study the function of the lncRNA BHLHE40-AS1 to determine the mechanism by which it is supporting the change from a benign to aggressive breast cancer. This proposal directly focuses on two Fiscal Year 2014 Breast Cancer Research Program Overarching Challenges. Specifically we aim to (1) distinguish aggressive from indolent breast cancers and use our findings to (2) identify why some breast cancers become life-threatening metastasis. In addressing these two challenges, we will also make progress towards ending the current state of overdiagnosis and overtreatment of breast cancer. Currently, there are procedures in place to diagnose what type of breast cancer a woman has, based on the presence or absence of specific genes in the tumor, and determine patient treatment strategies. If our study is successful in distinguishing aggressive from indolent cancers, we will identify genes that will allow us to predict which patients will require aggressive treatment. It would be possible to create an accompanying diagnostic test to help patients decide if they need to undergo surgery, radiation therapy, or simply monitor their disease progression. This could be realistically achieved in the next 10 years. Thus, it is our goal to empower patients by better informing their treatment options. In addition to allowing us to predict which patients can be spared aggressive treatment, these studies will also begin to teach us how lncRNAs facilitate tumor cells to become invasive and metastatic. Understanding these mechanisms will help identify new potential drug targets, or therapeutic entry points, to help treat those patients whose cancer has already progressed. Thus, the proposed study will impact breast cancer patients at multiple stages. In the short term, this study has the potential to improve early-stage patients quality of l
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510495
Entities
People
- Rebecca Sinnott
Organizations
- State University of New York at Albany
- United States Army